Japanese multicenter data regarding infective endocarditis and its prophylaxis

    Japanese multicenter data regarding infective endocarditis and its prophylaxis Koichiro Niwa PII: DOI: Reference:

S1058-9813(15)00048-X doi: 10.1016/j.ppedcard.2015.10.015 PPC 871

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Progress in Pediatric cardiology

Please cite this article as: Niwa Koichiro, Japanese multicenter data regarding infective endocarditis and its prophylaxis, Progress in Pediatric cardiology (2015), doi: 10.1016/j.ppedcard.2015.10.015

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Japanese Multicenter Data regarding Infective Endocarditis and Its Prophylaxis

Koichiro Niwa MD, PhD, FACC, FAHA, FJCC

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Cardiovascular Center St Luke’s International Hospital Tokyo, Japan

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Introduction

The incidence of infective endocarditis (IE) in patients with congenital heart disease

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(CHD) is increasing, especially in infants and adults with previous cardiac surgery. In spite of recent developments of prevention and diagnosis and medical and surgical management in CHD patients with IE, complications are still frequent and mortality

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rates are significant (1-8). Because of the high mortality of IE in patients with CHD, it is mandatory to establish formal recommendations for management and especially

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prevention (if possible) in CHD based on a large database. In this article, I will show data on the Japanese multicenter study (5) and the AHA recommendations (9). Finally, I

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will discuss on the prophylaxis of IE especially in moderate risk patients with CHD. Incidence of IE in CHD in Japan

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212 patients with CHD and IE were found from a total of 50,985 hospitalized patients with CHD from 2000-2005, and the prevalence of CHD and IE was 0.42% (212/50985: 1/240 admissions) (4). Demographic Data Detailed data in 239 CHD patients with IE from a 66 institutional database were collected (5); these included 170 children with CHD, age 7±6 years (14 days-17 years); (23 children: without apparent underlying HD); and 69 adults with CHD, age 33±14 (18-69) years. The male/female ratio was 143/96 (=1.49). Perioperative IE was observed in 28/119 (24%). Recurrent IE was in 21/229 (9.2%).

Their age distribution

is shown in Figure 1. The number of patients less than age 15 was high, possibly because the institutions involved in this dataset were those belonging to the Society of Japanese Pediatric Cardiology and Cardiovascular Surgery. Many patients followed by 1

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only community cardiologists were possibly missing.

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CHD Diagnoses

These data are shown in Table 1. Previous cardiac surgery had been performed in

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119/216 (55%) including reparative surgery in 75 and palliative surgery in 44. There were 90 cyanotic CHDs (unoperated: 6, palliated: 41, repaired: 43) and 124 acyanotic

Causative Microorganism (Table 2)

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CHDs (unoperated: 89, palliated: 3, repaired: 32)

A microorganism was identified in 201/239 (84%). The most frequent causative

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microorganism was streptococcus species (50%), followed by staphylococcus species, and MRSA was identified in 15 (8%).

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Mortality (Table 3)

The total mortality was 8.8% (21/239): Medical therapy alone: 14/176 (8%); Surgery in The mortality in

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active IE: 7/63 (11.1%); Surgery after recovery from IE: 0/40 (0%).

children was 16/170 (9.4%) and in adults was 5/69 (7.2%). Mortality in cases with prosthetic material infection including 12 urgent surgery cases was slightly higher; 3/26 Background CHD was identified in 18/21; unoperated in 3, palliated in 6 and

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(11.5%).

repaired in 9. Atrioventricular septal defect and double outlet right ventricle had the

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highest mortality. High risk CHD had high mortality, but mortality was as high even in VSD patients at 3/80 (3.8%). Causes of Death The causes of death in 21 patients were as follows: at surgery in 7; cardiac failure in 6 (including 2 with cerebral embolization); IE unresponsive to antibiotics therapy in 6, followed by pneumonia in 1 and renal failure in 1. Preceding Conditions & Procedures (Table 4) Preceding conditions & procedures in patients who developed IE were identified in 78/234 (33%). Of these, invasive dental procedures were most frequent (29/78 (37.2%) and details of dental procedures were identified in 24/29: tooth extraction in 12; and dental procedure for tooth caries including procedure for periodontitis in 12. 2

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CHD and IE after an Invasive Dental Procedure (Table 5)

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Most frequent CHD was ventricular septal defect (VSD) (11/24: 46%), followed by

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bicuspid aortic valve (4/24: 16.7%).

Prophylactic Antibiotics in Patients with Previous Invasive Dental Procedure (n=24) (Table 6)

Antibiotic prophylaxis was administered in only 3/24. No prophylactic antibiotics were

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prescribed in 21/24.

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Knowledge of IE in ACHD Patients and Their Parents (Table 7) Knowledge of IE and CHD is lower in ACHD patients compared with their parents.

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References of mortality in VSD with IE

Mortality of VSD and IE ranged from 1-13% in several reported series (Table 8)

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(5,7,10-12). Discussion

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The use of antimicrobial prophylaxis for IE has been drastically changed since the publication of the American Heart Association (AHA) guidelines in 2007 (9) and the

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European Society of Cardiology (ESC) guidelines in 2009 (13). These guidelines stated that IE prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE. Therefore, for example, a patient with an unrepaired VSD is not the target CHD that required IE prophylaxis of antibiotics (9,13-15). The Importance of Prophylaxis Prophylaxis for IE is very important for the following reasons; ① IE is life-threatening, and thus, prevention of IE is preferable to treatment; ② Some underlying cardiac conditions are at high risk to develop IE; ③ Bacteremia with microorganisms known to cause IE can occur during and after invasive dental procedures; ④ Antibiotic prophylaxis was proven to be effective for prevention of experimental IE. Thus, we believe that prevention of IE is important. For practical prevention of IE, the following 3

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issues are important; ① identification of risk factors for IE, ② identification of high risk groups for developing IE (1,6,15),③ identification of high risk procedures and

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treatment,④ Education of patients regarding importance of IE and daily dental care and

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antimicrobial prophylaxis. Guidelines on Prophylaxis for IE

Prophylaxis for IE has been recommended by guidelines in different countries in different years (AHA, ESC, Japanese Circulation Society) (9,13,16). Until the 2007

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AHA guidelines, antibiotic prophylaxis was recommended for most patients with repaired complex CHD and unrepaired CHD except for patients with atrial septal

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defects. Revised AHA Guidelines

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In 2007, the AHA guidelines on IE were revised dramatically (9). The guidelines reflected analyses of relevant literature regarding medical and surgical procedures, in

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vitro susceptibility data of the most common microorganisms that cause infective endocarditis, and the results of retrospective and prospective studies of prevention. The recommendations published were Class IIb, that is “usefulness/efficacy is less well

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established by expert opinion and case studies”. The major changes include the following: ① only an extremely small number of cases of IE might be prevented by

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antibiotic prophylaxis for dental procedures. ② IE prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome. ③ Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of IE.

The high risk categories of cardiac

conditions are as follows; prosthetic cardiac valves, previous IE, unrepaired cyanotic CHD, completely repaired CHD with prosthetic material or device during the first 6 months after the procedure, repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device. Except for these conditions, antibiotic prophylaxis is no longer recommended for any other form of CHD. The rationale of the revision was: ① IE is much more likely to result from frequent exposure to random bacteremia associated with daily activities than from bacteremia caused by a dental procedure.② Prophylaxis may prevent an exceedingly small number

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of cases of IE following a dental procedure. ③The risk of antibiotic-associated adverse events exceeds the benefit. ④Maintenance of optimal oral health and hygiene may

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reduce the incidence of bacteremia; ⑤ Usefulness/efficacy of prophylaxis is less well established and not validated.

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According to the ESC guidelines on IE in 2009 (13), antibiotic prophylaxis is also recommended only for patients with the highest risk of IE undergoing the highest risk dental procedures. Good oral hygiene and regular dental review are felt to have a very important role in reducing the risk of IE.

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After guidelines in the USA and Europe have substantially reduced the number of patients for whom antibiotic prophylaxis is recommended (1,17,18), the incidence of IE

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seems to have been increasing, but that may not be clinically significant, because the increase may be following the projected historical trend (1,10,12,13,17). No evidence was found that release of new antibiotic prophylaxis guidelines was associated with a

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significant change in IE admissions across 37 US children's hospitals (17). Recently, there is a report (18) on Incidence of IE in UK after 2009 guidelines. They analyzed

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data for the prescription of antibiotic prophylaxis from Jan 1, 2004, to March 31, 2013, and hospital discharge episode statistics for patients with IE from Jan 1, 2000, to March 31, 2013, and compared incidence of IE before and after NICE (the National Institute

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for Health and Clinical Excellence) guidelines in 2009. They found prescriptions of antibiotic prophylaxis fell substantially after the NICE guidelines (mean 10 900

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prescriptions/month [Jan 1, 2004, to March 31, 2008] vs 2236 prescriptions/month [April 1, 2008, to March 31, 2013], p<0·0001). Starting in March, 2008, the number of cases of IE increased significantly above the projected historical trend, by 0·11 cases per 10 million people per month (95% CI 0·05—0·16, p<0·0001). By March, 2013, 35 more cases per month were reported than would have been expected had the previous trend continued. Confirmation of the effectiveness of the new guidelines is important, but the incidence of IE is low, so that is rather difficult.

The main problem with these new

recommendations is that they were based, not on new data (18), but also on expert consensus opinion. National Multicenter Study of CHD and IE in Japan The prevalence of IE in children and adults with CHD is apparently increasing recently 5

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(1-8,19-22). In our Japanese survey, the prevalence of CHD and IE was 0.71% of hospitalized patients with CHD (4). The number of adults with CHD and IE is also

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increasing (8,23,24). The incidence of IE in complex cyanotic CHD has been increasing in France (14% of total IE in <1990 to 28% in >1990)(26). In CHD and IE, right-sided

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IE is frequent, so pulmonary emboli are not rare. The knowledge of prophylaxis in adolescents and young adults with CHD is sometimes very poor, therefore, proper

Antimicrobial Agents and Side Effects

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prophylaxis is often not performed (7-9).

The side effects of an antimicrobial agent may be no more than transient gastrointestinal

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problems and facial flushing. Anaphylaxis is very rare, as the AHA guidelines mentioned. One time use of antibiotics during dental procedure is supportive for patients, dentists, and internists to keep in mind the importance of IE and its prophylaxis.

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It might possibly effective not just prevention of developing IE, but frequently remind patients for prophylaxis (Table 7). One time use of antibiotics does not develop

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treatment of IE itself.

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antibiotic resistant bacteria. Also, the cost of antibiotics is not high comparing with the

IE in Patients with Ventricular Septal Defects Complex CHD such as cyanotic CHD regardless of repair is undoubtedly high risk

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when they were suffering with IE. The mortality is also high. However, in VSD that is thought not to be high risk by AHA guidelines, complications such as vegetation, pulmonary emboli are not rare. From an American report (19), the mortality of patients with IE under 21 years of age is as low as 1% (1/97). In our Japanese multicenter study on CHD and IE, the mortality was 3.8% (3/80). In several other reports, the lesion underlying IE included VSD patients in 2-13% (Table 6,5,7,10-12). Reparative surgery for VSD patients is safer than allowing them to develop IE. Also in young children, the mortality is a bit higher (5,8,23).

Considering both complications and mortality, we

believe that VSD patients are not low risk when they develop IE. In CHD (n=24) patients who developed IE after an invasive dental procedure, VSD was most frequent lesion (11/24,46%) followed by BAV (4/24, 16.7%)(Table 5). The number of complex CHD was rather small (4/24, 16.6%). In 78/216 (36.1%) of patients with CHD and IE, a preceding invasive procedure was identified (Table 4), and many episodes occur in 6

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patients in a moderate risk category of CHD. Rather than a failure of prophylaxis in our series, almost all patients (21/24, 87.7%) had not been given antibiotics at the time of

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invasive dental procedures. There are no studies comparing the incidence of IE between those with prophylactic antibiotics and those without. Since the AHA guidelines

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recommend antibiotic prophylaxis in patients with high risk CHD, are they not agreeing that IE prophylaxis is effective?

The Importance of Daily Dental Care for IE Prophylaxis

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Antibiotic prophylaxis is, of course, not enough to prevent IE. Daily dental care and skin care is very important. Both the AHA and Japanese guidelines emphasized this.

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Also patient education regarding prophylaxis is mandatory, especially on adolescent and

9) Future Considerations

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young adults, and this information needs to be repeated regularly.

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Data concerning IE in CHD are scarce and frequently associated with a selection bias. The current guidelines are largely based on expert opinion because of the low incidence

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of the disease, the absence of randomized trials, and the limited number of meta-analyses. Thus, the levels of evidence of current recommendations are low. The

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concept of antibiotic prophylaxis during procedures at risk is not evidence based. A randomized controlled multicenter trial should be necessary to prove the effectiveness of prophylaxis in future. Also, epidemiological surveys must be done to monitor guidelines on IE epidemiology.

Conclusions In our Japanese survey (4), the incidence of IE in moderate risk patients with CHD such as VSD after invasive dental procedure is not low, and morbidity and mortality can occur.

In our study, the incidence of CHD and IE after dental procedure was highest in

ventricular septal defect patients followed by bicuspid aortic valve patients, and the incidence of complex CHD was rather low. Almost none of our patients with IE had taken antibiotics at the time of invasive dental procedures. The incidence of side effects

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with antibiotic prophylaxis is low, especially in comparison with the cost of treating a patient with IE. Patients’ knowledge and practice of good oral health maintenance is not

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satisfactory. Repeated reminders and education by their providers is very important. In a recent report form UK, the incidence of IE has been increasing after 2008. We believe

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that more CHD patients should take antibiotics at the time of invasive dental procedures, even those at moderate risk (8,13).

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Conflict of Interest: None

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Role of Funding: None Figure legends

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Age distribution is shown. Incidence of patients less than age of 15 was high.

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Table 1 Diagnoses of underlying congenital heart disease Total (%)

No

(n= 216)

Operation

Repaired

Palliated

(n=75)

(n=44)

81 (37.5)

65

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Diagnosis

Tetralogy of Fallot ± PA

39 (18.1)**

3

19

17

Single ventricle/Fontan

22 (8.8)

3

7

12

Double outlet right ventricle

13 (7.4)

5

8

Mitral stenosis/ regurgitation

15 (6.9)

Aortic stenosis/regurgitation

11 (5.1)

d-TGA

8 (3.7)

COA, COA VSD

6 (2.8)

Atrioventricular septal defect

5 (2.3)

Congenitally corrected TGA

5 (2.3)

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Atrial septal defect

2 (0.9) 1 (0.5) 1 (0.5)

6

2

6 1

2

Valsalva aneurysm

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4

2 (0.9) 2 (0.9)

HLHS

7

2

Truncus arteriosus communis Ebstein’s Disease

3

3 (1.4)

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Patent ductus arteriosus

16

12

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VSD, VSD*

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(n=97)

4

1

4

1

1 2

2 1 Norwood: 1

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A-P, aortopulmonary; AVR, aortic valve replacement; AVP, aortic valve plasty; BAV, bicuspid aortic valve; COA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; ICR, intracardiac repair; MVP, mitral valve repair; MVR, mitral valve replacement; PAB, pulmonary artery banding; SCLF, subclavian flap; TCPC, total cavopulmonary connection; TGA, transposition of the great arteries; TVR, tricuspid valve repair; UF, unifocalization; VSD, ventricular septal defect. *: VSD plus atrial septal defect or patent ductus arteriosus, **: Tetralogy of Fallot and pulmonary atresia: 22.

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Table 2 Causative microorganisms Patients (%)(n=201)

Streptococcus species

100(49.8)

Alpha-streptococcus

87 (43.3) 11(5.5)

Beta-streptococcus

2(1.0)

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Pneumonia

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Organism

Staphylococcus species

74 (36.8)

Staphylococcus aureus

64 (31.8) 15 (7.5)

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MRSA Epidermidis

10 (5.0) 4 (2.0)

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MRSE Hemophilus sp Candida sp

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Pseudomonas Others

9 (4.5) 5 (2.5) 4 (2) 9 (4.5)

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MRSA, methicillin resistant staphylococcus aureus; MRSE, methicillin resistant staphylococcus epidermidis. Causative microorganism unknown:

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38. Others: Granulicatella 3, Micrococcus species 1, Moraxella species 1,

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Gamella species1, Enterococci 1, Bacillus 1, Anerobe species 1.

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Table 3 Diagnosis of CHD and mortality Mortality (n=18); deceased /total patients

Tetralogy of Fallot (VSD with PS)

1/39 (7.1%): repaired: 1,

Tetralogy of Fallot (VSD with PA)

4/28 (14.3%): repaired: 2 , palliated: 2

Double outlet right ventricle

4/16 (25%): repaired:2, palliated:2

Ventricular septal defect

3/80 (3.8%): no operation: 3

Single ventricle

2/19 (11%):

Atrioventricular septal defect

2/5 (40%): repaired: 2

DTGA

1/8 (12.5%): post Rastelli: 1

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Diagnosis

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post palliated: 2

Mitral regurgitation

1/14 (7.1%): repaired 1

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VSD: ventricular septal defect, PS: pulmonary stenosis, PA: pulmonary atresia, dTGA:

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complete transposition of the great arteries.

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Table 4 Conditions and procedures in those with infective endocarditis Patients (%), (n=78)

Invasive dental procedures

29 (37.2)

Cardiovascular surgery

20 (25.6)

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Conditions and procedures

Pneumonia

11 (14.1)

Invasive otolaryngeal procedures

5 (6.4)

Unexpected trauma

4 (5.1) 4 (5.1)

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Atopic dermatitis Central venous catheter

2(2.6)

1 (1.3)

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Catheter intervention Meningitis

1 (1.3)

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Piercing (cosmetic)

1 (1.3)

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Patients

Ventricular septal defect

11/24 (46%)

BAV (AR:2, AS:1, rep COA+AR:1)

4/24 (16.7%)

DORV w palliative surgery

1/24 (4.2%)

Single ventricle w palliative surgery

1/24 (4.2%)

DOLV w palliative surgery

1/24 (4.2%)

dTGA w Rastelli

1/24 (4.2%)

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Diagnosis

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Table 5 CHDs those developed IE after invasive dental procedure (n=24)

1/24 (4.2%)

No obvious background heart disease

4/24 (16.7%)

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Mitral regurgitation

CHD: congenital heart disease, BAV: bicuspid aortic valve, AR: aortic regurgitation, COA: coarctation of the aorta, DORV: double outlet right ventricle, DOLV: double outlet left

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ventricle, dTGA: complete transposition of the great arteries

Table 6 Prophylactic antibiotics in patients with previous invasive dental Antibiotics

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procedure

Patients (n=24) 1 (4.1%)

Antibiotics, name and dose unkown

2 (8.2)

None

21 (87.7%)

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cefaclor：600mg/day for 3 day

Table 7 Knowledge of infective endocarditis in ACHD patients and their parents Parents (n=497)

ACHmean age: ACHD patients (n=125)

Age

39±8 yrs

22 ±7 yrs

Knowledge of congenital heart disease

467/497 (94%)

108/125 (86%)

Knowledge of Iinfective endocarditis

288/497 (58%)

60/125 (48%)

ACHD: adult congenital heart disease

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Table 8 References on mortality in ventricular septal defect with infective endocarditis Patients

Death

Mortality

Reference

80

3

3.8%

97

1

1%

Day MD. Circulation 2009;119:865

47

1

2%

Shah P. Circulation 1966:34:127

31

1

3%

Li W. Euro Heart J 1998;19:166

32

4

13%

Gersony WM. Circulation 1993;87:I-121

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ED

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Niwa K. Heart 2005;91:795

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